Pharmacology/Drug Development

Preclinical opioid research using animal models not only provides mechanistic insights into the modulation of opioid analgesia and its associated side effects, but also validates drug candidates for improved treatment options for opioid use disorder. Non-human primates (NHPs) have served as a surrogate species for humans in opioid research for more than five decades. The translational value of NHP models is supported by the documented species differences between rodents and primates regarding their behavioral and physiological responses to opioid-related ligands and that NHP studies have provided more concordant results with human studies. This review highlights the utilization of NHP models in five aspects of opioid research, i.e., analgesia, abuse liability, respiratory depression, physical dependence, and pruritus. Recent NHP studies have found that (1) mixed mu opioid and nociceptin/orphanin FQ peptide receptor partial agonists appear to be safe, non-addictive analgesics and (2) mu opioid receptor- and mixed opioid receptor subtype-based medications remain the only two classes of drugs that are effective in alleviating opioid-induced adverse effects. Given the recent advances in pharmaceutical sciences and discoveries of novel targets, NHP studies are posed to identify the translational gap and validate therapeutic targets for the treatment of opioid use disorder. Pharmacological studies using NHPs along with multiple outcome measures (e.g., behavior, physiologic function, and neuroimaging) will continue to facilitate the research and development of improved medications to curb the opioid epidemic.

Local anesthetics are still incompletely understood, and none of the currently available drugs are optimal. The primary target of local anesthetics is the voltage-gated sodium channel (VGSC), where they lead to a temporary interruption of nerve conduction. Unfortunately, local anesthetics are neither specific at blocking a specific VGSC isoform, nor a specific cell type. We realize now that the old classification of A and C fibers according to myelin thickness is outdated, that next to differing myelin configuration, cells differ also by their molecular biology, and that there are close to 20 different neuronal subgroups when function is concerned. The ideal local anesthetic would only block sensory impulses, or even only painful impulses. In the search for that drug, several research avenues have been followed. First, efforts have been undertaken to extend duration of local anesthetics, by additives or extended-release formulation. Second, blockade of specific pain fibers has been attempted by targeting permanently charged anesthetics specifically into nociceptors. Third, blockade of specific isoforms using antibodies, and adaptation of naturally occurring neurotoxins has shown promise. Lastly, combination of local anesthetics with other analgesics may improve their duration of action.

The role of lipids in modulating membrane protein function is an emerging and rapidly growing area of research. The rational design of lipids that target membrane proteins for the treatment of pathological conditions is a novel extension in this field and provides a step forward in our understanding of membrane transporters. Bioactive lipids show considerable promise as analgesics for the treatment of chronic pain and bind to a high-affinity allosteric binding site on the human glycine transporter 2 (GlyT2 or SLC6A5). Here we use a combination of medicinal chemistry, electrophysiology, and computational modelling to develop a rational structure activity relationship for lipid inhibitors and demonstrate the key role of the lipid tail interactions for GlyT2 inhibition. Specifically, we examine how lipid inhibitor head group stereochemistry, tail length and double bond position promote enhanced inhibition. Overall, the L-stereoisomer is generally a better inhibitor than the D-stereoisomer, longer tail length correlates with greater potency, and the position of the double bond influences the activity of the inhibitor. We propose that the binding of the lipid inhibitor deep into the allosteric binding pocket is critical for inhibition. Furthermore, this provides insight into the mechanism of inhibition of GlyT2 and highlights how lipids can modulate the activity of membrane proteins by binding to cavities between helices. The principles identified in this work have broader implications for the development of a larger class of compounds that could target SLC6 transporters for disease treatment.